The goal of this proposal is to design immunogens for preventing infections with the human immunodeficiency virus (HIV-1). Such immunogens are expected to elicit immune responses eliminating HIV-1 and HIV-infected cells both of which can transmit disease. The components of such a response include: (1) antibodies which: (a) are virus-neutralizing (VNAb) and (b) participate in antibody- and complement-mediated cytotoxicity (ADCC and ACC, the production of which is dependent on generations of specific helper T (Th) cells; and (2) cytotoxic T (Tc) cells. The high variability in the sequence of HIV-1 envelope glycoproteins gp120 and gp41 between distinct HIV-1 isolates and the subtype specificity of early VNAb responses suggested that the production of broadly protective HIV-1 immunogens may be difficult. They propose to design multicomponent synthetic peptide immunogens eliciting broad VNAb, ADCC, ACC and HIV-1-specific Th and Tc cell responses. To select the appropriate peptides for such immunogens, they propose to carry out detailed studies on the immunochemical cross-reactivity between selected B- and T-cell epitopes of HIV-1 glycoproteins gp120/gp41 considering both the sequence variability in these viral proteins and the HLA restriction of immune responsiveness to these epitopes. The components of the proposed immunogens include: peptides corresponding to (a) hypervariable loops of the gp120 sequence (corresponding to residues 303-338 in the isolate IIIB) selected on the basis of immunological cross-reactivity from a limited number of HIV-1 isolates; (b) major T helper cell determinants; and (c) one or two additional peptides eliciting virus-neutralizing and/or cytotoxic antibodies.